The enzyme aromatase (CYP 19) is highly expressed in adipose tissue, where it converts testosterone to estradiol. In human overweight or obesity, excess adipose tissue is associated with excess aromatase activity, which in turn results in higher levels of estradiol in both men and women. In overweight and obese men, the relative excess of estradiol can feed back to the hypothalamic pituitary axis, suppressing gonadotropin secretion and thereby suppressing testicular testosterone production as well as spermatogenesis. Thus, severe obesity is associated with relative androgen deficiency in men. This condition can be called OHH or obese hypogonadotropic hypogonadism or hypogonadotropic hypogonadism in obese men.
In the 1999-2002 National Health and Nutrition Examination Survey data set, 27.5% of men over the age of 20 in the United States had a Body Mass Index (BMI) above 30 kg/m2. The prevalence of obesity is expected to continue to increase in the United States, and in both developed and developing countries around the world. In one study of 160 men referred for medical or surgical treatment of obesity, hypogonadotropic hypogonadism was present in 36% overall. In this study, the prevalence of hypogonadotropic hypogonadism rose linearly from 7.4% in those with a BMI of 30-35 kg/m2 to 59.2% in those with a BMI above 50 kg/m2 [Hofstra, et al 2008]. Based on the prevalence of obesity, we estimate that up to 1.5 million men in the US and 1 million men in Europe would have androgen deficiency due to hypogonadotropic hypogonadism.
The consequences of testosterone deficiency are many, including symptoms of decreased libido, decreased spontaneous erections, decreased fertility, loss of body hair and reduced shaving, low bone mineral density, increased risk of fractures, decreased muscle mass and strength and fatigue [Bhasin, et al 2006]. In addition, more recent studies have demonstrated that testosterone deficiency in older men and in men with obesity is also associated with metabolic abnormalities including insulin resistance, glucose intolerance, and lipid abnormalities, contributing to an increased incidence of metabolic syndrome, and likely increased risk of cardiovascular disease. In one study, up to 15% of diabetic men had clear hypogonadism (testosterone <300 ng/dL or <8 nmol/L) and up to 50% had testosterone in the lower range of normal (<12 nmol/L or <450 ng/dL) [Kapoor, et al 2006 and 2007]. An association has been established between low testosterone levels and various cardiovascular risk factors. Recent epidemiological studies have also linked low testosterone with cardiovascular mortality [Maggio et al. 2009].
Guidelines for the treatment of male hypogonadism have been developed by several organizations, including the Endocrine Society of the United States stating that “We recommend testosterone therapy for symptomatic men with androgen deficiency, who have low testosterone levels, to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density” [Bhasin, et al 2006]. Replacement of testosterone is typically recommended by either intramuscular or transdermal routes as the standard of care for men with documented hypogonadism (testosterone <300 ng/dL associated with symptoms of low testosterone) and can normalize libido, muscle mass and strength [Bhasin, et al 2006]. In addition, testosterone replacement improves insulin resistance in men with hypogonadism [Naharci, et al 2007].
Next to overweight and obesity and its associated excess aromatase activity, other causes of hypogonadism in men include primary testicular failure, which may be due to endogenous defects or acquired due to trauma, infection, or chemo- or radiation therapy, and secondary failures with suppression of gonadotropins that may be due to stress, concomitant diseases, or hypothalamic pituitary disorders.
Current therapies for testosterone deficiency are limited. Most hypogonadal men are treated with intramuscular injections of testosterone every 2 to 4 weeks, typically requiring a visit to a health care provider. Some men choose testosterone gels or patches that are usually applied daily. Men with OHH desiring fertility may be treated with intramuscular or subcutaneous injections of HCG or gonadotropins. There are various complications of testosterone replacement which may include gynecomastia due to the excessive conversion of exogenous testosterone to estradiol, infertility due to suppression of gonadotropins, mood swings due to the rise and fall of testosterone after intramuscular injections, and injection site or application site irritation. Excess testosterone can lead to polycythemia (erythrocytosis), prostate enlargement, sleep apnea, and worsening heart failure, in addition to aggressiveness. The Endocrine Society recommends “against starting testosterone therapy in patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen greater than 3 ng/ml without further urological evaluation, erythrocytosis (hematocrit >50%), hyperviscosity, untreated obstructive sleep apnea, severe lower urinary tract symptoms with International Prostate Symptom Score (IPSS) [Barry, et al 1992] greater than 19, or class III or IV heart failure.”, and that “men receiving testosterone therapy should be monitored using a standardized plan” [Bhasin, et al 2006].
Oral androgen therapies are generally contraindicated because of first pass hepatic effects that dramatically suppress HDL, increase thrombogenic factors, and often cause liver function abnormalities. These hepatic effects of androgens have also so far limited the clinical utility of selective androgen receptor modulators (SARMs).
Some commercially available aromatase inhibitors have also been tested for efficacy in hypogonadal men in a few, small proof of concept studies. Letrozole, given at doses of 2.5 mg weekly, increased total testosterone into the normal range, suppressed total estradiol, and increased LH and FSH in 12 OHH men [de Boer, et al 2005, Loves, et al 2008]. At this fixed dosing interval, free testosterone rose above the normal range in approximately half of the subjects. Other investigators have assessed the effects of aromatase inhibitors (letrozole [de Boer, et al 2005, Lapauw, et al 2009, Loves, et al 2008] CGS 20267 [Trunet, et al 1993] and anastrozole [Medras, et al 2007]) in uncontrolled studies.
One potential draw-back of all clinical studies conducted so far is that the aromatase inhibitors used in studies—anastrozole and letrozole—were developed for the treatment of hormone dependent cancers such as breast cancer in post-menopausal women and might therefore not be optimally suitable to treat hypogonadism in male patients, in particular in view of the optimal dosages and dosing regimen, and the potential side effects. Dosages and dosing regimens assessed so far in the clinical trials comprised the weekly administration of 2.5 mg or 1 mg of the respective aromatase inhibitor for the treatment of hypogonadism—which corresponds to the dosages used for adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer, but not an optimized treatment regimen for hypogonadism.
Indeed, human PK/PD studies of marketed aromatase inhibitors in men with hypogonadism have shown that e.g. letrozole at a 2.5 mg weekly dose resulted in excessive free testosterone levels in approximately half the subjects [Loves, et al, 2008]. There have been no studies so far to fully assess the effects of aromatase inhibitors on testosterone levels and how to actually achieve normalization of testosterone levels in men with hypogonadism.
Thus, optimized treatment regimens providing the relief of the testosterone deficiency driven symptoms of hypogonadism with minimal side effects are required. The development of an aromatase inhibitor especially suited for male patients with decreased testosterone levels would provide a novel treatment option for this so far insufficiently targeted disease.
In addition to the clinically approved non-steroidal aromatase Inhibitors anastrozole, letrozole and fadrozole, which are approved for the treatment of hormone dependent breast cancer by daily administration of dosages in the mg range, several other aromatase inhibitors have been described in the patent and scientific literature. One of these compounds is the aromatase inhibitor 4,4′-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile, also known as 4-[α-4-Cyanophenyl)-α-fluoro-1-(1,2,4-triazolyl)methyl]-benzonitrile or CGP47645, first described in 1992 [EP 490 816 and U.S. Pat. No. 5,637,605], having the following structural formula

CGP47645 is a fluoro-derivative of letrozole with a prolonged duration of action. Preliminary in-vitro and in-vivo experiments with this compound in rats and monkeys showed a similar up to 10 fold higher potency of aromatase inhibition as letrozole, and demonstrated the potential for less than daily treatment regimen. A once weekly administration of 3 mg/kg of CGP47645 was considered as an effective dose achieving medical castration in adult female rats [Batzl-Hartmann et al, 1994]. It was concluded that the half-life of CGP47645 is long enough to maintain endocrine efficacy similar to that of ovariectomy with a once-weekly dosing schedule [Bhatnagar et al, 1996]. However, no further studies of this drug compound have been carried out and its potential for the treatment of hormone dependent cancers or other diseases such as endometriosis was never investigated.
Currently, there are no oral pharmacological treatment regimens approved to treat hypogonadism and/or testosterone deficiency in obese male patients in the US and most other countries. As set out above, currently, testosterone, HCG or gonadotropin injections are so far the only option for these patients. Therefore, there is an important unmet medical need in this population for the development of a pharmacological treatment that reduces the disorders and symptoms associated with testosterone deficiency.
In particular, an oral therapy that normalizes systemic testosterone, but does not significantly increase local hepatic exposure to androgens would be highly desirable. In addition, it would be desirable to have a treatment regimen available achieving a more physiologic testosterone replacement.
In consideration of all problems and disadvantages connected with the so far known treatment options for male hypogonadism and testosterone deficiency, in particular hypogonadotropic hypogonadism in obese or overweight men, it would be highly advantageous to provide a new treatment option overcoming the aforementioned drawbacks and indeed providing relief or at least improvement for these patients.